Age-related macular degeneration (AMD) is a leading cause of blindness in the United States. Replacement of damaged cells with healthy retinal cells is a promising approach to the treatment of this, and other, retinal diseases. However, many obstacles must be overcome before transplantation will be clinically feasible. Our goal is to identify the critical immunological problems in RPE transplantation. using transgenic mice. Our first specific aim is to develop a transplant model in which the nominal antigen is defined and one in which rejection can be mediated by T cells from TCR transgenic mice specific for the defined antigen. These transgenic mice have OVA-specific T cells expressing the TCR transgene that is either MHC class I restricted (OT-I) or MHC class II restricted (OT-II). Our intention is to use RPE cells of OVA transgenic mice as donors for transplantation either directly into the TCR transgenic mice or syngeneic B6 mice with adoptive transfer of TCR transgenic cells. Our second specific aim is to produce a transgenic mouse model system that more realistically reflects the situation with AMD. These transgenic mice will be constructed such that the RPE can be ablated prior to transplantation. A construct consisting of the thymidine kinase (TK) gene under the regulation of the tyrosinase-related-protein- 1(TRP-1) promoter will be made. TK produced in pigmented cells with convert a prodrug, ganciclovir, into an active from that will subsequently kill the mammalian cells expressing this gene, thereby providing a more realistic environment or RPE transplantation.